Did you ever wonder how keratinocytes at the bottom of the epidermis turn into squames at the top of the horny layer? They follow the same process that happens when, starting with a fertilized egg, we end up with a healthy human being. Biochemically speaking, we can say that in both cases, starting with a cell having well defined characteristics, the organ or the organism ends up with different cells containing different proteins and metabolites. This process is called differentiation.

Differentiation is governed by the genes encoded in the DNA. Genes carry the information necessary to produce proteins. We call gene expression the process according to which the proteins are synthetized. Not all the genes are expressed in the same time. Gene expression is controlled by finely tuned mechanisms. In the vast majority of animals, plants and microorganisms, gene expression occurs when the DNA is “transcribed” (copied) into a messenger RNA (mRNA) that is then “translated” into proteins.

The first step in gene expression is the binding to DNA of an enzyme called RNA polymerase. This binding occurs at very particular sites of the DNA, that are “recognized” by the RNA polymerase. The binding depends on several parameters such as the sequence and the structure of the site, the presence of proteins that hinder or favor the binding, the concentration of ions such as sodium or calcium. In some instances, environmental factors such as lactose, high temperature, heavy metals, ultraviolet radiation, etc., can provoke the transcription of genes that would otherwise remain dormant. For instance, in E. coli cells, the addition of lactose induces the expression of the enzyme Beta-galactosidase; in fruit fly cells, increasing the temperature induces the expression of the so-called heat-shock proteins, a family of proteins committed to the repair or the removal of damaged proteins.

Other factors (such as darkness, oddly enough!) can indirectly hinder the expression of certain genes. Indeed, visible light inhibits the action of the enzymes that synthetize melatonin, which is synthetized in the dark.

Melatonin inhibits the transcription of the 5-lipoxygenase gene, a gene involved in the onset of inflammation; therefore, we can say that darkness represses the expression of the 5-lipoxygenase gene.
Scientists have recognized mechanisms of negative and positive controls of gene expression in bacteria, yeast and human beings; the mechanisms that are best known among skin care professionals are HSTF, AP-2, JNK, NF-kB and FOXO.

Epigenetics and Aging
It appears that the very first step in the process of gene expression is dictated by the physical chemistry or the stereochemistry of the binding of RNA polymerase to DNA. Not unexpectedly, chemical modifications of the DNA itself can play a role in controlling gene expression.

For instance, in bacteria and yeast, DNA damage such as pyrimidine dimers and single strand nicks do induce the expression of genes committed to DNA repair.

In organisms such as the human being, it has been observed that, in the course of aging, there is accumulation of methylated cytosines. Cytosines bound to methyl groups modify the chemistry and the stereo-chemistry of the DNA and can play a role in modulating the binding of RNA polymerase.

The relevance of the methylation of cytosines is highlighted by the fact that the methylation of cytosine occurs in neural cells in the course of the process of learning.

It has been observed that the pattern of DNA methylation can be altered in the fetus during pregnancy, when the environmental conditions are quite harsh; e.g., famine, maternal diseases. Some scientists have suggested that these modifications of the DNA can affect the first step of transcription (inducing or inhibiting the expression of genes) and that these effects could be protracted in time.

This particular action of the environment on the very chemical properties of the DNA is called “epigenetics” and we see that, in practice, it is nothing but one of the many mechanisms of “controlling” gene expression, even if nowadays many use the word epigenetic to mean the whole of the control of gene expression.

Other mechanisms do control the first step of expression of genes. In cells of higher organisms (humans, yeast, etc.), the DNA is tightly bound to a set of proteins called histones to form a compact body called chromatin.

To be transcribed, DNA must be detached from the histones, at least locally. Enzymes within the sirtuin family can remove a negatively-charged acetyl group from the histones, thus making them more positively charged.

DNA is a negatively-charged polymer and after the de-acetylation of the histones, it becomes more tightly bound to them. The RNA polymerase cannot bind to DNA and gene expression will be inhibited or silenced (Sirtuins are human enzymes analog to the Silent Information Regulation 2 -SIR 2 - proteins of yeast).

Once the RNA polymerase is bound to its specific sites in the DNA, it starts synthesizing the messenger RNA (mRNA) by copying one strand of the DNA. There is still time for other “controller” of gene expression to act. Anti-sense RNA in bacteria and micro RNA (miRNA) in eukaryotic cells can bind to the nascent messenger RNA chain and hinder its interaction with the ribosomes where the mRNA is translated into proteins. Let’s not confuse miRNA and mRNA!

Technically, the inhibition of gene expression can occur also by acting on the ribosomes, where proteins are manufactured. Cycloheximide, diphteria toxin and ricin are but examples of inhibitors of protein synthesis in higher organisms, as much as chloramphenicol, tetracycline and streptomycine are great inhibitors of protein synthesis in bacteria.

A Role in Skin Care
Why is all this infomration of interest to skin care researchers? There are several reasons. First of all, inducing the expression of specific genes in skin cells could be helpful for skin health. Indeed, as much as ultraviolet radiation induces the expression of specific genes in the epidermis, it should be possible to identify ingredients able to stimulate the expression of genes involved in the removal of UV-provoked damage. Since the level of filaggrin mRNA decreases with age, increasing the expression of filaggrin might help reduce dryness and itch, which are characteristic of aged skin.

Secondly, if we could induce the synthesis of the collagens (IV and VII) in the basement membrane of the epidermis, we could restore elasticity and resilience in aged skin.

Many examples can be found of impaired gene expression with age or in the aftermath of environmental or psychological stress; therefore, epigentics should be considered as a very relevant R&D topic in skin care.

Finally, if the US Food and Drug Administration (FDA) insists that inducers or inhibitors of gene expression are drugs, even when used only to restore the status quo ante, a cosmetic chemist can always take advantage of the knowledge accumulated on the control of gene expression in micro-organisms and on the characteristics of the skin microbiome, and design strategies aimed at favoring the growth of the beneficial flora to outgrow the harmful one.

Paolo Giacomoni acts as an independent consultant to the skin care industry. He served as executive director of research at Estée Lauder and was head of the department of biology with L’Oréal. He has built a record of achievements through research on DNA damage and metabolic impairment induced by UV radiation as well as on the positive effects of vitamins and antioxidants. He has authored more than 100 peer-reviewed publications and has more than 20 patents.

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